Globally, head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers, and affects ~500,000 individuals. In the US alone, oral cancer accounts for more deaths annually than cervical cancer, melanoma, or lymphoma. The 5-year survival rate is less than 50%, a prognosis that is poorer than breast cancer or melanoma. The poor prognosis of HNSCC is due to late detection;either due to poor visualization as in the posterior-lateral tongue;or due to an innocuous red or white clinical appearance that is easily confused with inflammation or irritation. Patients with late stage HNSCC receive highly aggressive surgical and radiation treatment, leading to loss of tissues such as the tongue and salivary glands. The surviving patient must confront monumental physical and emotional challenges that include facial disfiguration, feeding and speech impediments and poor quality of life. Although, a significant proportion of late stage tumors would have responded to chemotherapy/radiation (no surgery), no predictive parameters of treatment response exist. What is needed is a high throughput screening assay for HNSCC. Development of such knowledge will enhance detection of HNSCC and improve patient survival and quality of life. Patients with cancer produce antibodies against tumor-specific antigens, suggesting that these autoantibodies may have diagnostic and prognostic value. Preliminary data here indicate that a specific antibody repertoire can be identified for HNSCC. Defining the entire antibody repertoire produced against tumor antigens in HNSCC will lead to highly specific and sensitive multiplexed assays for detection of HNSCC. Thus, the central hypothesis of the proposed research is that the endogenous immune system can be harnessed as a biological "sensor" for detection of HNSCC. The objectives are to develop a HNSCC phage display library and to characterize the "humoral signature" for HNSCC using phage immunomic microarrays. PUBLIC HEALTH RELEVANCE: The poor prognosis of HNSCC is attributable to late detection;either due to poor visualization as in the posterior tongue;or to an innocuous red or white clinical appearance easily confused with irritation. Current oral cancer screening tests are inadequate, not specific, and poorly accessed. Patients with cancer produce antibodies against tumor-specific antigens, suggesting that these autoantibodies may have diagnostic and prognostic value. Thus, the endogenous immune system can be harnessed as a biological "sensor" for early detection of HNSCC. This will be accomplished by developing a HNSCC phage display library and immunomic microarrays and using these systems to characterize the humoral signature for HNSCC. This will lead to highly specific and sensitive multiplexed assays for early detection of HNSCC.